Withdrawal of parathyroid hormone after prolonged administration leads to adipogenic differentiation of mesenchymal precursors in vivo

Intermittent PTH-like drugs are the only approved so-called anabolic agent that increases bone mass in both mice and humans. It is well documented that PTH targets mature cells of the osteoblast lineage, with only indirect evidence of its actions on early cells of the osteoblast lineage. Using a triple transgenic mouse model that allowed labeling of very early cells of the osteoblast lineage, we traced the progeny of these into osteoblast lineage in adult mice. These early cells expressed PTH1R and multiplied when PTH (1-34) was administered daily. We also showed that the early mesenchymal cells showed accelerated differentiation into mature osteocalcin-positive osteoblasts and osteocytes. Rather surprisingly, when teriparatide administration was stopped, these early mesenchymal precursors differentiated into adipocytes. We showed that the adipogenic differentiation is accompanied by a decrease in wnt signaling in osteoblast precursors. In this review, we discuss the possible clinical relevance of this finding and the possible molecular mechanisms that contribute to this phenotype in vivo.